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Gene Review

Nfatc2  -  nuclear factor of activated T cells,...

Mus musculus

Synonyms: AI607462, NF-ATc2, NF-ATp, NFAT pre-existing subunit, NFAT1, ...
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Disease relevance of Nfatc2

  • Nfatc2(-/-) Nfatc4(-/-) mice are also protected from diet-induced obesity [1].
  • In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells [2].
  • Here we report that NFATp is also expressed in the rat PC12 pheochromocytoma cell line and in the murine nervous system [3].
  • Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts [4].
  • Recently, the calcium-activated phosphatase calcineurin (PP2B) and the family of transcription factors known as NFAT have been implicated in the regulation of myocyte hypertrophy and fiber type specificity [5].
  • Combined, these results reveal a major role for the NFATc2 transcription factor in pathological cardiac remodeling and heart failure [6].

High impact information on Nfatc2

  • We show that NFATc2 has pro migratory and pro invasive capabilities in breast cancer cells [7][8].
  • Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs [9] .
  • We show that the initiation of heart valve morphogenesis in mice requires calcineurin/NFAT to repress VEGF expression in the myocardium underlying the site of prospective valve formation [10].
  • Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex [11].
  • Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells [12].
  • Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts [13].

Biological context of Nfatc2


Anatomical context of Nfatc2

  • Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression [13].
  • The NF-AT complex consists of two components: NF-ATp, which pre-exists in the cytosol and whose appearance in the nucleus is induced by an increase of intracellular calcium, and a nuclear AP-1 component whose induction is dependent upon activation of protein kinase C (PKC) [16].
  • The widely used immunosuppressant agents cyclosporin and FK506 are thought to antagonize the immune response by directly inhibiting calcineurin-NFAT signal transduction in lymphocytes [17].
  • It has been reported that both NFAT1 and NFATx are required to maintain the homeostasis of the immune system [18].
  • In an in vivo model of allergic inflammation, the accumulation of eosinophils and levels of serum immunoglobulin E were increased in NFAT1 -/- mice [19].

Associations of Nfatc2 with chemical compounds

  • NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix [13].
  • Covalent modification of NIP45 by arginine methylation is an important mechanism of regulating the expression of NFAT-dependent cytokine genes [20].
  • A dominant negative NFAT molecule attenuates LPS- and IFN-gamma-activated endogenous IL-12 p40 mRNA expression [21].
  • Further, mutation of the threonine residue in this sequence to cysteine, as in Rel proteins, confers on NFATp a sensitivity to sulfhydryl modification similar to that of Rel family proteins [22].
  • One specific short sequence in NFATp (RAHYETEG), located near the NH2 terminus of the DNA-binding domain, resembles a highly conserved sequence (RFRYxCEG) that is located near the NH2 terminus of the Rel homology region and that has been implicated in DNA binding by Rel family proteins [22].
  • These results support the view that high NFAT activity is necessary for TNF-alpha and IL-13 promoter induction in MC, irrespective of whether NFATc2 or NFATc1 or a combination of both is present [23].

Physical interactions of Nfatc2


Regulatory relationships of Nfatc2

  • Nuclear factor of activated T cells (NFAT) is a transcription factor that regulates expression of the cytokine interleukin-2 (IL-2) in activated T cells [28].
  • These results suggest that IFN-gamma production by T cells is regulated by NFAT1, most likely at the level of gene transcription [29].
  • Whereas the binding of NFAT-1 and Octamer factors enhance the activity of the Il-4 promoter, the binding of HMG I(Y) suppresses its activity and, therefore, appears to be involved in the suppression of Il-4 transcription in resting T lymphocytes [24].
  • The activity NFAT proteins is regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a target for inhibition by CsA and FK506 [30].
  • A mechanism underlying this effect was suggested by the observation that JNK directly regulated nuclear factor of activated T-cell (NFAT) activation in culture and in transgenic mice containing an NFAT-dependent luciferase reporter [31].

Other interactions of Nfatc2


Analytical, diagnostic and therapeutic context of Nfatc2




  1. Role of transcription factor NFAT in glucose and insulin homeostasis. Yang, T.T., Suk, H.Y., Yang, X., Olabisi, O., Yu, R.Y., Durand, J., Jelicks, L.A., Kim, J.Y., Scherer, P.E., Wang, Y., Feng, Y., Rossetti, L., Graef, I.A., Crabtree, G.R., Chow, C.W. Mol. Cell. Biol. (2006) [Pubmed]
  2. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Hodge, M.R., Ranger, A.M., Charles de la Brousse, F., Hoey, T., Grusby, M.J., Glimcher, L.H. Immunity (1996) [Pubmed]
  3. Expression of the transcription factor NFATp in a neuronal cell line and in the murine nervous system. Ho, A.M., Jain, J., Rao, A., Hogan, P.G. J. Biol. Chem. (1994) [Pubmed]
  4. Convergent signaling by acidosis and receptor activator of NF-kappaB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. Komarova, S.V., Pereverzev, A., Shum, J.W., Sims, S.M., Dixon, S.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  5. A calcineurin-NFATc3-dependent pathway regulates skeletal muscle differentiation and slow myosin heavy-chain expression. Delling, U., Tureckova, J., Lim, H.W., De Windt, L.J., Rotwein, P., Molkentin, J.D. Mol. Cell. Biol. (2000) [Pubmed]
  6. NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure. Bourajjaj, M., Armand, A.S., da Costa Martins, P.A., Weijts, B., van der Nagel, R., Heeneman, S., Wehrens, X.H., De Windt, L.J. J. Biol. Chem. (2008) [Pubmed]
  7. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Jauliac, S., López-Rodriguez, C., Shaw, L.M., Brown, L.F., Rao, A., Toker, A. Nat. Cell. Biol. (2002) [Pubmed]
  8. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Yoeli-Lerner, M., Yiu, G.K., Rabinovitz, I., Erhardt, P., Jauliac, S., Toker, A. Mol. Cell. (2005) [Pubmed]
  9. FOXP3 controls regulatory T cell function through cooperation with NFAT. Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A.D., Stroud, J.C., Bates, D.L., Guo, L., Han, A., Ziegler, S.F., Mathis, D., Benoist, C., Chen, L., Rao, A. Cell (2006) [Pubmed]
  10. A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Chang, C.P., Neilson, J.R., Bayle, J.H., Gestwicki, J.E., Kuo, A., Stankunas, K., Graef, I.A., Crabtree, G.R. Cell (2004) [Pubmed]
  11. Transcriptional mechanisms underlying lymphocyte tolerance. Macián, F., García-Cózar, F., Im, S.H., Horton, H.F., Byrne, M.C., Rao, A. Cell (2002) [Pubmed]
  12. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Ho, I.C., Hodge, M.R., Rooney, J.W., Glimcher, L.H. Cell (1996) [Pubmed]
  13. NFAT and Osterix cooperatively regulate bone formation. Koga, T., Matsui, Y., Asagiri, M., Kodama, T., de Crombrugghe, B., Nakashima, K., Takayanagi, H. Nat. Med. (2005) [Pubmed]
  14. The transcription factor NFAT4 is involved in the generation and survival of T cells. Oukka, M., Ho, I.C., de la Brousse, F.C., Hoey, T., Grusby, M.J., Glimcher, L.H. Immunity (1998) [Pubmed]
  15. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Ranger, A.M., Oukka, M., Rengarajan, J., Glimcher, L.H. Immunity (1998) [Pubmed]
  16. A common factor regulates both Th1- and Th2-specific cytokine gene expression. Rooney, J.W., Hodge, M.R., McCaffrey, P.G., Rao, A., Glimcher, L.H. EMBO J. (1994) [Pubmed]
  17. Defective T cell development and function in calcineurin A beta -deficient mice. Bueno, O.F., Brandt, E.B., Rothenberg, M.E., Molkentin, J.D. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  18. Role of NFATx (NFAT4/NFATc3) in expression of immunoregulatory genes in murine peripheral CD4+ T cells. Chen, J., Amasaki, Y., Kamogawa, Y., Nagoya, M., Arai, N., Arai, K., Miyatake, S. J. Immunol. (2003) [Pubmed]
  19. An enhanced immune response in mice lacking the transcription factor NFAT1. Xanthoudakis, S., Viola, J.P., Shaw, K.T., Luo, C., Wallace, J.D., Bozza, P.T., Luk, D.C., Curran, T., Rao, A. Science (1996) [Pubmed]
  20. Arginine methylation of NIP45 modulates cytokine gene expression in effector T lymphocytes. Mowen, K.A., Schurter, B.T., Fathman, J.W., David, M., Glimcher, L.H. Mol. Cell (2004) [Pubmed]
  21. Activation of the murine interleukin-12 p40 promoter by functional interactions between NFAT and ICSBP. Zhu, C., Rao, K., Xiong, H., Gagnidze, K., Li, F., Horvath, C., Plevy, S. J. Biol. Chem. (2003) [Pubmed]
  22. A similar DNA-binding motif in NFAT family proteins and the Rel homology region. Jain, J., Burgeon, E., Badalian, T.M., Hogan, P.G., Rao, A. J. Biol. Chem. (1995) [Pubmed]
  23. Specific and redundant roles for NFAT transcription factors in the expression of mast cell-derived cytokines. Klein, M., Klein-Hessling, S., Palmetshofer, A., Serfling, E., Tertilt, C., Bopp, T., Heib, V., Becker, M., Taube, C., Schild, H., Schmitt, E., Stassen, M. J. Immunol. (2006) [Pubmed]
  24. Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter. Chuvpilo, S., Schomberg, C., Gerwig, R., Heinfling, A., Reeves, R., Grummt, F., Serfling, E. Nucleic Acids Res. (1993) [Pubmed]
  25. Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling. Chakkalakal, J.V., Stocksley, M.A., Harrison, M.A., Angus, L.M., Deschenes-Furry, J., St-Pierre, S., Megeney, L.A., Chin, E.R., Michel, R.N., Jasmin, B.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  26. p21ras function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells. Woodrow, M.A., Rayter, S., Downward, J., Cantrell, D.A. J. Immunol. (1993) [Pubmed]
  27. Impaired AP-1 dimers and NFAT complex formation in immature thymocytes during in vivo glucocorticoid-induced apoptosis. Wisniewska, M., Pyrzynska, B., Kaminska, B. Cell Biol. Int. (2004) [Pubmed]
  28. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. McCaffrey, P.G., Luo, C., Kerppola, T.K., Jain, J., Badalian, T.M., Ho, A.M., Burgeon, E., Lane, W.S., Lambert, J.N., Curran, T. Science (1993) [Pubmed]
  29. Regulation of interferon-gamma gene expression by nuclear factor of activated T cells. Kiani, A., García-Cózar, F.J., Habermann, I., Laforsch, S., Aebischer, T., Ehninger, G., Rao, A. Blood (2001) [Pubmed]
  30. Role of the cyclosporin-sensitive transcription factor NFAT1 in the allergic response. Viola, J.P., Rao, A. Mem. Inst. Oswaldo Cruz (1997) [Pubmed]
  31. c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signaling. Liang, Q., Bueno, O.F., Wilkins, B.J., Kuan, C.Y., Xia, Y., Molkentin, J.D. EMBO J. (2003) [Pubmed]
  32. Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. Ikeda, F., Nishimura, R., Matsubara, T., Tanaka, S., Inoue, J., Reddy, S.V., Hata, K., Yamashita, K., Hiraga, T., Watanabe, T., Kukita, T., Yoshioka, K., Rao, A., Yoneda, T. J. Clin. Invest. (2004) [Pubmed]
  33. PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis. Healy, A.M., Izmailova, E., Fitzgerald, M., Walker, R., Hattersley, M., Silva, M., Siebert, E., Terkelsen, J., Picarella, D., Pickard, M.D., LeClair, B., Chandra, S., Jaffee, B. J. Immunol. (2006) [Pubmed]
  34. Effect of staphylococcal enterotoxin B-induced anergy on cytokine gene expression: anergy-sensitive and resistant mRNA expression. Koide, Y., Uchijima, M., Yoshida, A., Yoshida, T.O. J. Interferon Cytokine Res. (1996) [Pubmed]
  35. Inefficient termination of antigen responses in NF-ATp-deficient mice. Heyer, J., Kneitz, B., Schuh, K., Jankevics, E., Siebelt, F., Schimpl, A., Serfling, E. Immunobiology (1997) [Pubmed]
  36. 3BP2 deficiency impairs the response of B cells, but not T cells, to antigen receptor ligation. de la Fuente, M.A., Kumar, L., Lu, B., Geha, R.S. Mol. Cell. Biol. (2006) [Pubmed]
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